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Liver cirrhosis is a chronic condition that is associated with a variety of complications across organ systems. Patients with cirrhosis also suffer from immune dysfunction, which may predispose them to catastrophic bacterial and fungal infections. Bacterial infections in liver cirrhosis have been well-documented, however, data remains scarce regarding fungal infections. Candida and Aspergillus have been reported as the most common pathogens among patients with cirrhosis, causing both invasive and non-invasive infections. However, other pathogens such as Coccidioides, Pneumocystis, Cryptococcus, and Rhizopus have been increasing in incidence. Diagnosis of fungal infection is often difficult, particularly in regards to distinguishing colonization from invasive infection. Serum markers such as beta-D-glucan (BDG) and galactomannan are beneficial diagnostic tools in conjunction with fungal cultures and imaging modalities. Bronchoscopy with bronchoalveolar lavage (BAL) or lung biopsy can be useful adjuncts as well. Liver transplantation is another important consideration as invasive fungal infection (IFI) is a contraindication to transplant surgery. Additionally, patients are at increased risk for infection due to immunosuppression in the post-transplant period. We aim to discuss the mechanisms responsible for immune dysfunction in advanced liver disease, the epidemiology of fungal infections in this population, as well as presentations and management considerations pertaining to specific pathogens and antifungal regimens.

We propose a general framework for studying two-dimensional (2D) topologically ordered states subject to local correlated errors and show that the resulting mixed-state can display intrinsically mixed-state topological order (imTO) -- topological order which is not expected to occur in the ground state of 2D local gapped Hamiltonians. Specifically, we show that decoherence, previously interpreted as anyon condensation in a doubled Hilbert space, is more naturally phrased as, and provides a physical mechanism for, "gauging out" anyons in the original Hilbert space. We find that gauging out anyons generically results in imTO, with the decohered mixed-state strongly symmetric under certain anomalous 1-form symmetries. This framework lays bare a striking connection between the decohered density matrix and topological subsystem codes, which can appear as anomalous surface states of 3D topological orders. Through a series of examples, we show that the decohered state can display a classical memory, encode logical qubits (i.e., exhibit a quantum memory), and even host chiral or non-modular topological order. We argue that the decohered states represent genuine mixed-state quantum phases of matter and that a partial classification of imTO is given in terms of braided fusion categories., Comment: 14 pages, 2 figures. Both authors contributed equally to this work. v2: typos fixed and references updated

Background: Currently all participants of the Dutch colorectal cancer (CRC) screening program with a positive faecal immunochemical test (FIT) are seen at the outpatient clinic to assess their health status, receive information on colonoscopy and CRC risk, and provide informed consent. However, for many patients this information could probably also safely be exchanged in an online setting, in order to reduce the burden for patients, healthcare system, and environment. In this study we will evaluate if a face-to-face pre-colonoscopy consultation can be replaced by a Digital Intake Tool (DIT) in a CRC screening population. Methods: This is a prospective multicentre single-arm, non-randomized study with a non-inferiority design. The DIT will triage a total of 1000 participants and inform them about CRC risk, colonoscopy, sedation, and provide bowel preparation instructions. Participants identified as high-risk (i.e., red-triaged) will be contacted by phone or scheduled for an appointment at the outpatient clinic. The primary outcome measure will be adequate bowel preparation rate, defined as the proportion of participants with a Boston Bowel Preparation (BBPS) score ≥ 6. To compare our primary outcome, we will use colonoscopy data from 1000 FIT positive participants who visited the outpatient clinic for pre-colonoscopy consultation. Secondary outcomes will include participation rate, colonoscopy adherence rate, patient experience in terms of satisfaction and anxiety, knowledge transfer, number of outpatient visits that can be averted by the DIT, and cost-effectiveness of the tool. Ethical approval was obtained from the Medical Ethical Committee of the Erasmus Medical Center (MEC-2021-0098). Discussion: This study aims to assess if a face-to-face pre-colonoscopy consultation can be replaced by an eHealth assessment and education tool in a FIT-based CRC screening program. In case favourable results are established, the intervention evaluated in this study could signif

Radiation‑induced normal tissue toxicity is a common acute and chronic outcome of radiotherapy (RT) for prostate cancer (PCa). There are currently no existing pre‑assessments before treatment to predict acute and late RT‑induced toxicity. Novel predictive blood biomarkers in radiation oncology may improve treatment decision‑making and therapeutic monitoring for patients with PCa. A comprehensive systematic search of microRNA (miRNA/miR) profiling studies published in PubMed, Science Direct and Google Scholar was performed. The present systematic review, supported by meta‑analysis, summarises key findings and discusses the results of prospective clinical studies investigating miRNA expression levels and their association with RT‑induced toxicity in PCa. Out of seven clinical studies, six highlighted levels of 10 miRNAs changing in plasma, serum or peripheral blood mononuclear cells during RT. The post‑RT expression levels of miRNA‑132‑5p, miRNA‑1‑3p, miRNA‑410 and miRNA‑221 were increased, and miRNA‑23a‑3p expression was decreased among patients with low‑grade RT‑induced toxicity. Furthermore, in patients with high‑grade RT toxicity, miRNA‑197‑3p, miRNA‑151a‑5p, miRNA‑18b‑5p, miRNA‑99a and miRNA‑21 expression was increased, while miRNA‑132‑5p expression was decreased. The present miRNA meta‑analysis could be the focus of future studies to identify their potential clinical value as PCa biomarkers and therapeutic mediators in RT‑induced toxicity. The variations in miRNA levels post‑RT could be used as predictive biomarkers of RT‑induced toxicity. However, further extensive validation is required to establish the relationship between miRNA expression levels and RT‑induced toxicity in PCa and to confirm their predictive value.

Background: Not being in employment, education, or training (NEET) is associated with poor health (physical and mental) and social exclusion. We investigated whether England’s statutory school readiness measure conducted at 4–5 years provides a risk signal for NEET in late adolescence. Methods: We identified 8,118 individuals with school readiness measures at 4–5 years and NEET records at 16–17 years using Connected Bradford, a bank of linked routinely collected datasets. Children were categorised as ‘school ready’ if they reached a ‘Good Level of Development’ on the Early Years Foundation Stage Profile. We used probit regression and structural equation modelling to investigate the relationship between school readiness and NEET status and whether it primarily relates to academic attainment. Results: School readiness was significantly associated with NEET status. A larger proportion of young people who were not school ready were later NEET (11%) compared to those who were school ready (4%). Most of this effect was attributable to shared relationships with academic attainment, but there was also a direct effect. Measures of deprivation and Special Educational Needs were also strong predictors of NEET status. Conclusions: NEET risk factors occur early in life. School readiness measures could be used as early indicators of risk, with interventions targeted to prevent the long-term physical and mental health problems associated with NEET, especially in disadvantaged areas. Primary schools are therefore well placed to be public health partners in early intervention strategies.

BackgroundStudies have reported that the COVID-19 pandemic has led to an increase in alcohol consumption and alcohol-associated health problems in the general population. Our previous study documented a rise in severe alcohol-related hepatitis cases requiring inpatient admission in our hospital system in the early pandemic (2019 vs. 2020). This study assesses the rates of severe alcohol-related hepatitis in the latter part of the pandemic (2021).MethodsWe performed a retrospective chart review via an electronic medical record to evaluate the number of cases of alcohol-related hepatitis in patients presenting to three community hospitals in Fresno, California, between 2019 (pre-pandemic) and 2021. A total of 547 patients were included in the study. We compared the demographics, clinical course, and outcomes of patients with alcohol-related hepatitis pre-pandemic (2019), early pandemic (2020), and during the later phase of the pandemic (2021).ResultsThe number of cases increased from 131 in 2019 to 201 in 2020 and 215 in 2021 (53% and 64% increase, respectively). The number of young patients (age <40 years) increased from 30 in 2019 to 61 in 2020 and 71 in 2021 (103% and 136% increase, respectively) (p = 0.13). The number of admissions of women increased from 24 in 2019 to 55 in 2020 and 67 in 2021 (129% and 179% increase, respectively) (p = 0.026). Deaths during hospitalization increased from 20 in 2019 to 26 in 2021 (p = 0.674). The number of rehospitalizations within 3 months increased 4.5 times from 18 in 2019 to 80 in 2021 (p < 0.001).ConclusionOur study revealed that the admissions for alcohol-related hepatitis remained significantly above the pre-pandemic levels through the end of 2021. We believe this sustained increase in cases of alcohol-related hepatitis in our hospital system reflects a much larger national problem. Alcohol-related hepatitis is associated with significant morbidity, mortality, and societal cost. Urgent p

ObjectivesThe concept of frailty has gained importance, especially in patients with liver disease. Our study systematically investigated the effect of frailty on post-procedural outcomes in patients undergoing transjugular intrahepatic portosystemic shunt (TIPS).MethodsWe used National Inpatient Sample(NIS) 2016-2019 data to identify patients who underwent TIPS. Hospital frailty risk score (HFRS) was used to classify patients as frail (HFRS>=5) and non-frail (HFRS<5). The relationship between frailty and outcomes such as death, post-procedural shock, non-home discharge, length of stay (LOS), post-procedural LOS, and total hospitalization charges (THC) was assessed.ResultsA total of 13,700 patients underwent TIPS during 2016-2019. Of them, 5,995 (43.76%) patients were frail, while 7,705 (56.24%) were non-frail. There were no significant differences between the two groups based on age, gender, race, insurance, and income. Frail patients had higher mortality (15.18% vs. 2.07%, p<0.001), a higher incidence of non-home discharge (53.38% vs. 19.08%, p<0.001), a longer overall LOS (12.5 days vs. 3.35,p<0.001), longer post-procedural stay (8.2 days vs. 3.4 days, p<0.001), and higher THC ($240,746.7 vs. $121,763.1, p<0.001) compared to the non-frail patients. On multivariate analysis, frail patients had a statistically significant higher risk of mortality (aOR-3.22, 95% CI-1.98- 5.00, p<0.001).ConclusionFrailty assessment can be beneficial in risk stratification in patients undergoing TIPS.

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic was a public health crisis affecting medical, social, and psychological wellness. In a previous study, we reported a rise in alcohol-related hepatitis (ARH) cases between 2019 and 2020 in the central valley of California. Our goal in the current study was to assess the impact of COVID-19 on ARH at a national level.Materials and methodsWe used data from the 2016 to 2020 National Inpatient Sample. All adult patients diagnosed with ARH (ICD10 K70.1 and K70.4) were included. Information was collected regarding patient demographics, hospital characteristics, and severity of hospitalization. We analyzed the annual percentage changes (PC) between 2016-2019 and 2019-2020 to assess the impact of COVID-19 on hospitalizations. Multivariate logistic regression analysis was performed to identify factors associated with increased ARH admissions between 2016 and 2020.ResultsA total of 823,145 patients were admitted with ARH. The total number of cases increased from 146,370 in 2016 to 168,970 in 2019 (annual percentage change (PC) 5.1%), while the cases increased to 190,770 in 2020 (PC 12.4%). The PC in women was 6.6% between 2016 and 2019, which increased to 14.2% between 2019 and 2020. In men, PC increased by 4.4% between 2016 and 2019 to 12.2% between 2019 and 2020. On multivariate analysis, after adjusting for patient demographics and hospital characteristics, there was 46% increased odds of admission with ARH in 2020, compared to 2016. The total number of deaths increased from 8725 in 2016 to 9190 in 2019 (PC 1.7%), while the total number of deaths increased to 11,455 in 2020 (PC 24.6%).ConclusionsA sharp rise in the cases of ARH between 2019 and 2020 was noted, which aligned with the COVID-19 pandemic. Not only did total hospitalization increase, but an increase in mortality was also noted, reflecting higher severity in the patients admitted during the COVID-19 pandemic.

BackgroundClinical experience suggests an increased hospitalization rate for alcohol-related hepatitis (AH) in the winter months; however, seasonal variations in the prevalence of hospitalizations for AH have not been described previously. We hypothesized that AH hospitalizations would be higher in the winter months due to the holiday season and increased alcohol sales.MethodsPatients with primary or secondary discharge diagnosis of AH were included in the study (International Classification of Diseases, Clinical Modification-10th Revision codes K70.4 and K70.1) between January 2016 and December 2019. The primary outcome measure for this study was daily hospitalizations by each month of the year. Secondary outcome measures included the rate of in-hospital mortality associated with AH, for each month.ResultsThe highest number of AH-related admissions was reported in July (n = 56,800; 9%), followed by August (n = 55,700; 8.8%) and May (n = 54,865; 8.7%). February had the lowest number of admissions (n = 46,550; 7.37%). The adjusted mortality was highest in December (overall mortality: 9.6%; adjusted odds ratio: 1.29; 95% confidence interval: 1.142 - 1.461; P < 0.0001) and lowest in May (overall mortality rate: 7.7%). No difference was noted between length of stay and total hospitalization cost between months.ConclusionOur findings demonstrate that seasonal variations in hospitalizations related to AH do exist across the United States. Regional differences also exist and follow unique patterns. The increase in admissions for AH is in line with other studies suggesting that heavy drinking happens during the warm season. Hospital administrators and other stewards of healthcare resources can use seasonal patterns to guide allocation of resources.

BackgroundAlcohol-related hepatitis is one of the most severe manifestations of alcohol-related liver disease and has been associated with significant morbidity, mortality and financial burden. Patients with alcohol use disorders are at risk of leaving against medical advice (LAMA); however, there is currently a lack of data in the literature to show which patients are at higher risk. In this study, we investigated the specific demographic factors and comorbidities associated with LAMA.MethodsPatients with a primary or secondary discharge diagnosis of alcohol-related hepatitis (ICD10-CM codes K70.4 and K70.1) between January 2016 and December 2019 were included in this study. Demographics, comorbidities, complications and interventions were studied in for patients who LAMA. Multivariate analysis was conducted to elucidate factors contributing to the increased risk of alcohol-related hepatitis.ResultsA total of 538,750 patients were admitted with a diagnosis of alcohol-related hepatitis. Of these, 31,500 (5.84%) patients LAMA. Older age, Hispanic race, private insurance, and higher income status were associated with a lower risk of LAMA, while younger age, African American race, lack of insurance and being in the lowest income quartile were associated with the highest risk.ConclusionsOur findings demonstrated that significant differences exist between patients with alcohol-related hepatitis who LAMA and those who remain hospitalized until discharge. We believe that this study will help healthcare providers identify patients at risk of LAMA, and help promote the targeted education of specific subgroups to improve their understanding of their disease state and decrease adverse events.

Background and aimThe third leading preventable cause of death in the United States is excessive alcohol consumption. Our study sought to assess the impact of the coronavirus disease 2019 (COVID-19) on hospitalizations for alcohol-related hepatitis at a community hospital system. We hypothesized an increase in cases of alcohol-related hepatitis requiring inpatient management, mirroring the strain on economic and societal norms imposed by the COVID-19 pandemic.Approach/resultsWe performed a retrospective chart review to study the incidence of alcohol-related hepatitis in patients presenting to 3 community hospitals in Fresno, California, before and during the COVID-19. Data including patient demographics, markers of disease severity, and clinical course were extracted from electronic medical records for 329 patients included in the study. There was a 51% increase in the overall incidence of alcohol-related hepatitis requiring hospitalization between 2019 and 2020 (P=0.003) and 69% increase (P<0.001) after implementation of the stay-at-home orders. In addition, 94% (P=0.028) increase in rehospitalizations was noted in 2020 (P=0.028), a 100% increase in patients under the age of 40 (P=0.0028), as well as a trend towards a 125% increase (P=0.06) of female patients admitted with this diagnosis during the COVID-19 pandemic.ConclusionsOur study revealed drastic increases in severe alcohol-related hepatitis requiring inpatient management, specifically in patients under the age of 40 and in women during the COVID-19 pandemic. Given the high morbidity and mortality associated with severe alcohol-related hepatitis, these findings have far-reaching and lasting implications for our already strained health care system extending beyond the COVID-19 pandemic timeframe. Urgent public health interventions are needed to combat the rising misuse of alcohol and its consequences.

Background & aimsThere are limited data regarding fibrosis progression in biopsy-proven nonalcoholic fatty liver disease (NAFLD) in people with type 2 diabetes mellitus (T2DM) compared with people without T2DM. We assessed the time to fibrosis progression in people with T2DM compared with people without T2DM in a large, multicenter, study of people with NAFLD who had paired liver biopsies.MethodsThis study included 447 adult participants (64% were female) with NAFLD who had paired liver biopsies more than 1 year apart. Liver histology was systematically assessed by a central pathology committee blinded to clinical data. The primary outcome was the cumulative incidence of a ≥1-stage increase in fibrosis in participants with T2DM compared with participants without T2DM.ResultsThe mean (SD) age and body mass index (calculated as weight in kilograms divided by the square of the height in meters) were 50.9 (11.5) years and 34.7 (6.3), respectively. The median time between biopsies was 3.3 years (interquartile range, 1.8-6.1 years). Participants with T2DM had a significantly higher cumulative incidence of fibrosis progression at 4 years (24% vs 20%), 8 years (60% vs 50%), and 12 years (93% vs 76%) (P = .005). Using a multivariable Cox proportional hazards model adjusted for multiple confounders, T2DM remained an independent predictor of fibrosis progression (adjusted hazard ratio, 1.69; 95% CI, 1.17-2.43; P = .005). The cumulative incidence of fibrosis regression by ≥1 stage was similar in participants with T2DM compared with participants without T2DM (P = .24).ConclusionsIn this large, multicenter cohort study of well-characterized participants with NAFLD and paired liver biopsies, we found that fibrosis progressed faster in participants with T2DM compared with participants without T2DM. These data have important implications for clinical practice and trial design.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

The multipartite entanglement structure for the ground states of two dimensional topological phases is an interesting albeit not well understood question. Utilizing the bulk-boundary correspondence, the calculation of tripartite entanglement in 2d topological phases can be reduced to that of the vertex state, defined by the boundary conditions at the interfaces between spatial regions. In this paper, we use the conformal interface technique to calculate entanglement measures in the vertex state, which include area law terms, corner contributions, and topological pieces, and a possible additional order one contribution. This explains our previous observation of the Markov gap $h = \frac{c}{3} \ln 2$ in the 3-vertex state, and generalizes this result to the $p$-vertex state, general rational conformal field theories, and more choices of subsystems. Finally, we support our prediction by numerical evidence, finding precise agreement., Comment: 22 pages, 7 figures

BackgroundCOVID-19 is associated with higher morbidity and mortality in patients with chronic liver diseases (CLDs). However, our understanding of the long-term outcomes of COVID-19 in patients with CLD is limited.MethodsWe conducted a multicenter, observational cohort study of adult patients with CLD who were diagnosed with COVID-19 before May 30, 2020, to determine long-term clinical outcomes. We used a control group of patients with CLD confirmed negative for COVID-19.ResultsWe followed 666 patients with CLD (median age 58 years, 52.8% male) for a median of 384 (interquartile range: 31-462) days. The long-term mortality was 8.1%; with 3.6% experiencing delayed COVID-19-related mortality. Compared to a propensity-matched control group of patients with CLD without COVID-19 (n=1332), patients with CLD with COVID-19 had worse long-term survival [p<0.001; hazards ratio (HR): 1.69; 95% CI: 1.19-2.41] and higher rate of hospitalization (p<0.001, HR: 2.00, 1.62-2.48) over a 1-year follow-up period. Overall, 29.9% of patients reported symptoms of long-COVID-19. On multivariable analysis, female sex (p=0.05, HR: 2.45, 1.01-2.11), Hispanic ethnicity (p=0.003, HR: 1.94, 1.26-2.99), and severe COVID-19 requiring mechanical ventilation (p=0.028, HR: 1.74, 1.06-2.86) predicted long-COVID-19. In survivors, liver-related laboratory parameters showed significant improvement after COVID-19 resolution. COVID-19 vaccine status was available for 72% (n=470) of patients with CLD and history of COVID-19, of whom, 70% (n=326) had received the COVID-19 vaccine.ConclusionsOur large, longitudinal, multicenter study demonstrates a high burden of long-term mortality and morbidity in patients with CLD and COVID-19. Symptoms consistent with long-COVID-19 were present in 30% of patients with CLD. These results illustrate the prolonged implications of COVID-19 both for recovering patients and for health care systems.

Hemochromatosis is a genetic disorder marked by abnormally high levels of intestinal iron absorption leading to severe end-organ damage. It is classically associated with HFE gene mutations, including C282Y and H63D, but in recent years, many non-HFE mutations along with novel variants have been discovered, particularly among non-Whites. We describe a case of an elderly Japanese patient who was evaluated for markedly elevated ferritin found to have hemochromatosis, with no hepatic fibrosis while being negative for HFE and common non-HFE gene mutations.

Alcohol-related hepatitis (ARH) is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by significant alcohol use. It ranges in severity from mild to severe and carries significant morbidity and mortality. The refinement of scoring systems has enhanced prognostication and guidance of clinical decision-making in the treatment of this complex disease. Although treatment focuses on supportive care, steroids have shown benefit in select circumstances. There has been a recent interest in this disease process, as coronavirus disease 2019 pandemic led to substantial rise in cases. Although much is known regarding the pathogenesis, prognosis remains grim due to limited treatment options. This article summarizes the epidemiology, genetics, pathogenesis, diagnosis and treatment of ARH.

Changes in patterns of activity within the medial prefrontal cortex enable rodents, non-human primates and humans to update their behaviour to adapt to changes in the environment-for example, during cognitive tasks1-5. Parvalbumin-expressing inhibitory neurons in the medial prefrontal cortex are important for learning new strategies during a rule-shift task6-8, but the circuit interactions that switch prefrontal network dynamics from maintaining to updating task-related patterns of activity remain unknown. Here we describe a mechanism that links parvalbumin-expressing neurons, a new callosal inhibitory connection, and changes in task representations. Whereas nonspecifically inhibiting all callosal projections does not prevent mice from learning rule shifts or disrupt the evolution of activity patterns, selectively inhibiting only callosal projections of parvalbumin-expressing neurons impairs rule-shift learning, desynchronizes the gamma-frequency activity that is necessary for learning8 and suppresses the reorganization of prefrontal activity patterns that normally accompanies rule-shift learning. This dissociation reveals how callosal parvalbumin-expressing projections switch the operating mode of prefrontal circuits from maintenance to updating by transmitting gamma synchrony and gating the ability of other callosal inputs to maintain previously established neural representations. Thus, callosal projections originating from parvalbumin-expressing neurons represent a key circuit locus for understanding and correcting the deficits in behavioural flexibility and gamma synchrony that have been implicated in schizophrenia and related conditions9,10.

Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist.

Systemic inflammation is established as part of late-stage severe lung disease, but molecular, functional, and phenotypic changes in peripheral immune cells in early disease stages remain ill defined. Chronic obstructive pulmonary disease (COPD) is a major respiratory disease characterized by small-airway inflammation, emphysema, and severe breathing difficulties. Using single-cell analyses we demonstrate that blood neutrophils are already increased in early-stage COPD, and changes in molecular and functional neutrophil states correlate with lung function decline. Assessing neutrophils and their bone marrow precursors in a murine cigarette smoke exposure model identified similar molecular changes in blood neutrophils and precursor populations that also occur in the blood and lung. Our study shows that systemic molecular alterations in neutrophils and their precursors are part of early-stage COPD, a finding to be further explored for potential therapeutic targets and biomarkers for early diagnosis and patient stratification.

Toll-like receptor 7 (TLR7) is known for eliciting immunity against single-stranded RNA viruses, and is increased in both human and cigarette smoke (CS)-induced, experimental chronic obstructive pulmonary disease (COPD). Here we show that the severity of CS-induced emphysema and COPD is reduced in TLR7-deficient mice, while inhalation of imiquimod, a TLR7-agonist, induces emphysema without CS exposure. This imiquimod-induced emphysema is reduced in mice deficient in mast cell protease-6, or when wild-type mice are treated with the mast cell stabilizer, cromolyn. Furthermore, therapeutic treatment with anti-TLR7 monoclonal antibody suppresses CS-induced emphysema, experimental COPD and accumulation of pulmonary mast cells in mice. Lastly, TLR7 mRNA is increased in pre-existing datasets from patients with COPD, while TLR7+ mast cells are increased in COPD lungs and associated with severity of COPD. Our results thus support roles for TLR7 in mediating emphysema and COPD through mast cell activity, and may implicate TLR7 as a potential therapeutic target.

Objective: To investigate at a population level whether England’s universal assessment of ‘school readiness’ is associated with later identification of special educational needs (SEN). Also, whether ethnic differences exist in SEN identification (white British versus ethnic minority) and whether this varies as a function of school readiness. Method: Analysis included 53 229 individuals aged 5–12 years from the Connected Bradford Database (2012/2013–2019/2020). Logistic regression analyses examined: (1) whether reaching a ‘good level of development’ on England’s ‘school readiness’ assessment was associated with later SEN identification; and (2) whether interactions exist between school readiness and ethnicity. Results: 32 515 of 53 229 children reached a good level of development, of which 3036 (9.3%) were identified as having SEN. In contrast, 10 171 of 20 714 (49.1%) of children who did not reach a good level of development were later identified as having SEN. Children not reaching a good level of development had increased odds of being later identified as having SEN after controlling for covariates (OR: 8.50, 95% CI: 8.10 to 8.91). In children who did not reach a good level of development, white British children had higher odds of being identified as having SEN compared with ethnic minority peers (OR: 1.22, 95% CI: 1.11 to 1.34). No ethnic differences of having SEN were observed in children reaching a good level of development (OR: 1.04, 95% CI: 0.93 to 1.16). Conclusions: School readiness assessments are associated with later SEN identification. Structural inequalities may exist in SEN identification in children not entering formal education ‘school ready’. Such assessments could facilitate earlier identification of SEN and reduce structural inequalities in its identification.

Objective: We present strategies to perceived barriers to access to kidney transplantation (KT) in the Netherlands. Methods: This qualitative study (N = 70) includes nephrologists, social workers, surgeons, nurses, patients, former living kidney donors, policy employees, and insurance representatives. Interviews were conducted both in focus groups and individually and coded with NVivo. Results: Participants proposed strategies within five domains. 1.Policy: Making KT guideline more visible. 2.Medical: Increase access and transparency to KT medical eligibility criteria (e.g., age, BMI) for patients and healthcare providers. 3.Psychological: Support patients who continue to use dialysis because of social interaction opportunities associated with dialysis settings to find such interaction elsewhere. Link kidney patients with fears for KT to experienced experts or trained professionals. 4.Social: Support patients with language barriers with interpreters and visual explanations. Support patients using social media, e.g. Facebook, to identify potential donors. Better expectation management to reduce reports of inadequate aftercare for living donors. 5.Economical: Solving negative economic incentives for KT by changing incentives. Conclusion: Stakeholders see strategies for barriers in the entire care pathway. Innovation: This large qualitative study gives an important overview which strategies stakeholders see improving access to KT. Some strategies offer opportunities to solve barriers in the short-term.

Chronic obstructive pulmonary disease (COPD) is significant cause of morbidity and mortality worldwide. There is mounting evidence suggesting that COPD patients are at increased risk of severe COVID-19 outcomes; however, it remains unclear whether they are more susceptible to acquiring SARS-CoV-2 infection. In this comprehensive review, we aim to provide an up-to-date perspective of the intricate relationship between COPD and COVID-19. We conducted a thorough review of the literature to examine the evidence regarding the susceptibility of COPD patients to COVID-19 infection and the severity of their disease outcomes. While most studies have found that pre-existing COPD is associated with worse COVID-19 outcomes, some have yielded conflicting results. We also discuss confounding factors such as cigarette smoking, inhaled corticosteroids, and socioeconomic and genetic factors that may influence this association. Furthermore, we review acute COVID-19 management, treatment, rehabilitation, and recovery in COPD patients and how public health measures impact their care. In conclusion, while the association between COPD and COVID-19 is complex and requires further investigation, this review highlights the need for careful management of COPD patients during the pandemic to minimize the risk of severe COVID-19 outcomes.

Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist., Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist.

Aalam Sohal,1 Kris V Kowdley1,2 1Department of Hepatology, Liver Institute Northwest, Seattle, WA, USA; 2Department of Gastroenterology and Hepatology, Elson Floyd College of Medicine, Spokane, WA, USACorrespondence: Kris V Kowdley, Liver Institute Northwest, 3216 NE 45th Pl Suite 212, Seattle, WA, 98105, USA, Email kkowdley@liverinstitutenw.orgAbstract: Primary biliary cholangitis (PBC), previously referred to as primary biliary cirrhosis, is an autoimmune disorder leading to the destruction of intra-hepatic bile ducts. If untreated, progressive bile duct damage and cholestasis can lead to ductopenia and result in cirrhosis. Ursodiol, the first drug approved for PBC, has changed the natural history of this disease and improved patient outcomes. Subsequently, several new prediction models incorporating a response to ursodiol were developed. These include the GLOBE score, which was shown to predict long-term outcomes in patients with PBC. In 2016, obeticholic acid (OCA) became the second drug to be approved by the FDA, predominantly based on improvement in alkaline phosphatase (ALP) levels. This trial has subsequently influenced the design of clinical trials. Several drugs are currently being evaluated as therapeutic options for PBC, with improvement in ALP being a main endpoint. In this review, we will discuss the impact of new therapies on GLOBE scores in patients with PBC.Keywords: PBC, GLOBE scores, treatments, therapeutic options

Purpose: This paper introduces initial foundations of a sustainability-dominant logic theory intersecting the sustainable operations and supply chain management (SOSCM) discipline with the circular economy (CE) field of knowledge. Design/methodology/approach: The paper applies propositional forms of theorising to derive the formulation of propositions and interconnections that interrelate SOSCM and CE principles, concepts and practices which provide a reinforcing theoretical basis underlying the proposed sustainability-dominant logic theory. Findings: Key findings are represented by elaborated theoretical propositions for a sustainability-dominant logic linking SOSCM and CE principles, concepts and well-established practical assumptions. The initial set of propositions offers useful insights for a sustainability-dominant logic at three managerial levels: product, firm and supply chain level. Originality/value: The paper offers an original theoretical common ground based on a sustainability-dominant logic linking key SOSCM with CE tenets, this way developing SOSCM theory anchored in the CE paradigm and, conversely, developing CE theory supported by SOSCM principles and praxis. The initial set of propositions introduced in the paper provides a new pathway for future research and debate by OM scholars engaged with SOSCM and CE developments.

OBJECTIVES: The aim of this study was to obtain an in-depth perspective from stakeholders involved in access to kidney transplantation to pave the way for solutions in improving access to kidney transplantation. This study qualitatively explored factors influencing optimal access to kidney transplantation from a broad stakeholder perspective. DESIGN: A qualitative study was performed using semistructured interviews both in focus groups and with individual participants. All interviews were recorded, transcribed and coded according to the principles of grounded theory. SETTING: Participants were healthcare providers (geographically spread), patients and (former living) kidney donors, policy-makers and insurers. PARTICIPANTS: Stakeholders (N=87) were interviewed regarding their perceptions, opinions and attitudes regarding access to kidney transplantation. RESULTS: The problems identified by stakeholders within the domains-policy, medical, psychological, social and economic-were acknowledged by all respondents. According to respondents, more efforts should be made to make healthcare providers and patients aware of the clinical guideline for kidney transplantation. The same opinion applied to differences in medical inclusion criteria used in the different transplantation centres. Stakeholders saw room for improvement based on psychological and social themes, especially regarding the provision of information. Many stakeholders described the need to rethink the current economic model to improve access to kidney transplantation. This discussion led to a definition of the most urgent problems for which, according to the respondents, a solution must be sought to optimise access to kidney transplantation. CONCLUSIONS: Stakeholders indicated a high sense of urgency to solve barriers in patient access to kidney transplantation. Moreover, it appears that some barriers are quite straightforward to overcome; according to stakeholders, it is striking that this process has not ye

Purpose: This paper introduces initial foundations of a sustainability-dominant logic theory intersecting the sustainable operations and supply chain management (SOSCM) discipline with the circular economy (CE) field of knowledge. Design/methodology/approach: The paper applies propositional forms of theorising to derive the formulation of propositions and interconnections that interrelate SOSCM and CE principles, concepts and practices which provide a reinforcing theoretical basis underlying the proposed sustainability-dominant logic theory. Findings: Key findings are represented by elaborated theoretical propositions for a sustainability-dominant logic linking SOSCM and CE principles, concepts and well-established practical assumptions. The initial set of propositions offers useful insights for a sustainability-dominant logic at three managerial levels: product, firm and supply chain level. Originality/value: The paper offers an original theoretical common ground based on a sustainability-dominant logic linking key SOSCM with CE tenets, this way developing SOSCM theory anchored in the CE paradigm and, conversely, developing CE theory supported by SOSCM principles and praxis. The initial set of propositions introduced in the paper provides a new pathway for future research and debate by OM scholars engaged with SOSCM and CE developments.

The Netherlands was the first European country to implement unspecified kidney donation in 2000. This qualitative study aimed to evaluate the experiences of unspecified kidney donors (UKDs) in our transplant institute to improve the care for this valuable group of donors. We conducted semi-structured interviews with 106 UKDs who donated between 2000–2016 (response rate 84%). Interviews were audio-recorded, transcribed verbatim and independently coded by 2 researchers in NVivo using thematic analysis. The following 14 themes reflecting donor experiences were found: Satisfaction with donation; Support from social network; Interpersonal stress; Complaints about hospital care; Uncertainty about donor approval; Life on hold between approval and actual donation; Donation requires perseverance and commitment; Recovery took longer than expected; Normalization of the donation; Becoming an advocate for living kidney donation; Satisfaction with anonymity; Ongoing curiosity about outcome or recipient; Importance of anonymous communication; Anonymity is not watertight. The data reinforced that unspecified kidney donation is a positive experience for donors and that they were generally satisfied with the procedures. Most important complaints about the procedure concerned the length of the assessment procedure and the lack of acknowledgment for UKDs from both their recipients and health professionals. Suggestions are made to address the needs of UKDs.

BackgroundPediatric metabolic-associated fatty liver disease (MAFLD) is a global health problem, with lifestyle modification as its major therapeutic strategy. Rigorous characterization of dietary content on MAFLD in children is lacking. We hypothesized an objectively measured healthier diet would positively modulate MAFLD.MethodsDiet was assessed using the Nutrition Data System for Research in children enrolled from 10 tertiary clinical centers to determine the Healthy Eating Index (HEI, 0-100) and individual food components.ResultsIn all, 119 children were included (13.3 ± 2.7 y), 80 (67%) male, 67 (18%) White, and 90 (76%) Hispanic, with an average body mass index Z-score of 2.2 ± 0.5. Diet was classified as low HEI < 47.94 (n = 39), mid HEI ≥ 47.94 and < 58.89 (n = 41), or high HEI ≥ 58.89 (n=39). Children with high HEI (healthier diet) had lower body weight (p = 0.005) and more favorable lipids. Mean serum triglycerides for low, mid, and high HEI were 163, 148, and 120 mg/dL, respectively; p = 0.04 mid versus high, p = 0.01 low versus high. Mean HDL was 38, 41 and 43 mg/dL; p = 0.02 low vs high. Less severe steatosis was noted with added sugar ≤ 10% of calories (p = 0.03). Higher lobular inflammation is associated with a higher percentage of calories from fat (OR (95% CI) = 0.95 (0.91-1.00), p = 0.04).ConclusionsIn children with MAFLD, high HEI is associated with lower body weight and more favorable lipids, while added sugar and fat intake has individual histologic features. Differential consumption of major dietary components may modify both metabolic risk factors and histologic liver injury, highlighting the importance of objective diet assessments in children with MAFLD.

Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist., Pancreatic ductal adenocarcinoma (PDAC) has been left behind in the evolution of personalized medicine. Predictive markers of response to therapy are lacking in PDAC despite various histological and transcriptional classification schemes. We report an artificial intelligence (AI) approach to histologic feature examination that extracts a signature predictive of disease-specific survival (DSS) in patients with PDAC receiving adjuvant gemcitabine. We demonstrate that this AI-generated histologic signature is associated with outcomes following adjuvant gemcitabine, while three previously developed transcriptomic classification systems are not (n = 47). We externally validate this signature in an independent cohort of patients treated with adjuvant gemcitabine (n = 46). Finally, we demonstrate that the signature does not stratify survival outcomes in a third cohort of untreated patients (n = 161), suggesting that the signature is specifically predictive of treatment-related outcomes but is not generally prognostic. This imaging analysis pipeline has promise in the development of actionable markers in other clinical settings where few biomarkers currently exist.

Hepatic encephalopathy (HE) is a reversible brain dysfunction caused by liver insufficiency and portosystemic shunting. Hepatic encephalopathy is a common complication of advanced liver disease and is on a rise with the increasing incidence of non-alcoholic steatohepatitis (NASH). Since partnership with nursing staff is a critical part of successful management of these complex patients, we conducted a survey assessing their knowledge regarding HE.169 nurses participated in the survey. We found that more than 30% of the nurses did not know that ammonia is one of the toxins responsible for causing hepatic encephalopathy. We also found that 20% of the nurses had difficulty answering questions regarding titration of lactulose to bowel movements. Dietary education is a significant area for improvement as 80% of the nurses wanted to restrict fat and carbohydrate intake in these patients. With this simple survey, we identified important knowledge gaps among experienced nurses at our institution. We believe that by improving knowledge through focused lectures, we can improve patient care and reduce the length of hospitalizations in patients with HE.

BACKGROUND: Depression is pleiotropic and influenced by diverse genetic, environmental, and pharmacological factors. Identifying patterns of circuit activity on which many of these factors converge would be important, because studying these patterns could reveal underlying pathophysiological processes and/or novel therapies. Depression is commonly assumed to involve changes within prefrontal circuits, and dopamine D2 receptor (D2R) agonists are increasingly used as adjunctive antidepressants. Nevertheless, how D2Rs influence disease-relevant patterns of prefrontal circuit activity remains unknown. METHODS: We used brain slice calcium imaging to measure how patterns of prefrontal activity are modulated by D2Rs, antidepressants, and manipulations that increase depression susceptibility. To validate the idea that prefrontal D2Rs might contribute to antidepressant responses, we used optogenetic and genetic manipulations to test how dopamine, D2Rs, and D2R+ neurons contribute to stress-coping behavior. RESULTS: Patterns of positively correlated activity in prefrontal microcircuits are specifically enhanced by D2R stimulation as well as by two mechanistically distinct antidepressants, ketamine and fluoxetine. Conversely, this D2R-driven effect was disrupted in two etiologically distinct depression models, a genetic susceptibility model and mice that are susceptible to chronic social defeat. Phasic stimulation of dopaminergic afferents to the prefrontal cortex and closed-loop stimulation of D2R+ neurons increased effortful responses to tail suspension stress, whereas prefrontal D2R deletion reduced the duration of individual struggling episodes. CONCLUSIONS: Correlated prefrontal microcircuit activity represents a point of convergence for multiple depression-related manipulations. Prefrontal D2Rs enhance this activity. Through this mechanism, prefrontal D2Rs may promote network states associated with antidepressant actions and effortful responses to stress.